Total Synthesis of (+)-Acutiphycin† Ryan M. Moslin and Timothy F. Jamison* Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
[email protected] ReceiVed August 30, 2007
Synthetic studies toward the total synthesis of (+)-acutiphycin (1) resulted in the discovery of additivefree, highly regioselective nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes and the construction of an advanced intermediate in studies directed toward the synthesis of 1. Ultimately, although not employing the nickel-catalyzed reaction, a highly convergent total synthesis of (+)-acutiphycin featuring an intermolecular SmI2-mediated Reformatsky coupling reaction and macrolactonization initiated by a retro-ene reaction of an alkoxyalkyne was achieved. The resulting synthesis was 18 steps in the longest linear sequence from either methyl acetoacetate or isobutyraldehyde.
Introduction The complex macrolide (+)-acutiphycin (1) was isolated in 1984 by Moore and co-workers and possesses potent in vivo antineoplastic activity against murine Lewis lung carcinoma, as well as significant cytotoxicity against KB and NIH/ 3T3 cell lines.1 Since the natural source of acutiphycin (the blue-green alga Oscillatoria acutissima) no longer produces this metabolite, detailed investigations of its mechanism of action and therapeutic potential have been very limited, and further studies must be fueled by chemical synthesis. Smith et al. reported the first total synthesis of 1 in 1995,2 and a series of studies directed toward the total synthesis of 1 have also been described by Kiyooka et al.3 The strategies employed in both the Smith et al. synthesis and the Kiyooka et al. approach are * Corresponding author. Fax: (617) 324-0253. † This work is dedicated to Prof. Edward Piers on the occasion of his 70th birthday.
(1) Barchi, J. J., Jr.; Moore, R. E.; Patterson, F. M. L. J. Am. Chem. Soc. 1984, 106, 8193-8197. (2) (a) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1995, 117, 12013-12014. (b) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935-10946. (3) (a) Hena, M. A.; Kim, C.-S.; Horiike, M.; Kiyooka, S.-i. Tetrahedron Lett. 1999, 40, 1161-1164. (b) Kiyooka, S.-i.; Hena, M. A. J. Org. Chem. 1999, 64, 5511-5523.
linear in nature, whereas we recently reported the first convergent total synthesis of (+)-acutiphycin.4 Herein, we describe our initial strategy for the total synthesis of (+)-acutiphycin and the discoveries that resulted from this approach. A detailed description of the successful route to (+)-acutiphycin is also provided. The nickel-catalyzed reductive coupling of alkynes and aldehydes5 has been shown to be a versatile tool in the synthesis of natural products.6 Although regioselectivity is optimal for aromatic alkynes7 (Scheme 1, eq 1) and 1,3-enynes (Scheme 1, eq 2),8 good levels of regiocontrol have also been ob(4) Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1510615107. (5) For a review of nickel-catalyzed coupling processes, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890-3908. (b) Moslin, R. M.; Miller-Moslin, K. M.; Jamison, T. F. Chem. Comm. 2007, 44414449. (6) For representative examples of nickel-catalyzed reductive coupling reactions of aldehydes and alkynes in total synthesis: (a) Synthesis of (+)allopumiliotoxin 339A: Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098-6099. (b) Synthesis of (-)-terpestacin: Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 11514-11515. (c) Synthesis of (+)amphidinolide T1: Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998-999. (7) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442-3443. (8) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 1534215343. 10.1021/jo701821h CCC: $37.00 © 2007 American Chemical Society
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Published on Web 11/07/2007
Total Synthesis of (+)-Acutiphycin SCHEME 1. Nickel-Catalyzed Reductive Coupling Reactions of Alkynes
SCHEME 3.
Synthesis of Aldehyde Fragment 3
SCHEME 4. Synthesis of Enyne 5 via Indium-Mediated Addition of Prenyl Bromide
SCHEME 2.
Retrosynthetic Analysis of (+)-Acutiphycin
served for alkynes containing two distinct alkyl substituents (Scheme 1, eq 3).9 All of these transformations give exclusive syn additionto the alkyne, resulting in the formation of (E)trisubstituted allylic alcohols, and allows for the possibility of catalyst and/or reagent control. In our initial approach to (+)acutiphycin, we intended to form both of the (E)-trisubstituted olefins and to establish the configurations at C7 and C13 using these catalytic processes (Scheme 2). In addition, due to the challenges associated with macrolactonization en route to 1,2b we initially investigated an alternative C-C bond-forming strategy to close the macrocycle: nickel-catalyzed reductive macrocyclization. Although we considered both reductive coupling reactions to be challenging, the C14-C15 bond was targeted for the ring closing step since the range of oxidation states present along the C1-C7 backbone would make it difficult to reveal the C7 aldehyde. In contrast, the remaining C-C bond would be formed via Claisen condensation with acetate 6. (9) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156-166.
Results and Discussion The synthesis of the C2-C7 fragment began with enantiomerically enriched 7,10 a well-known intermediate available by alkylation of methyl acetoacetate and subsequent asymmetric reduction (Scheme 3).11,12 Protection of 7 as the silyl ether followed by reductive debenzylation and oxidation provided 3. Although hydroxyl groups have been shown to direct addition to aldehydes via chelation,13 we chose a nonchelating protective group, tert-butyldiphenylsilyl (TBDPS), since chelation control via hydroxyl groups has not, to date, been demonstrated in nickel-catalyzed reductive coupling reactions of alkynes and aldehydes.14 As shown in Scheme 4, enyne 5 (X ) CH2) was selected rather than 4 (X ) O) to avoid competitive reductive cyclization during the fragment coupling with 3, as well as other competing reactions in the Claisen condensation with 6. After the reductive coupling step, oxidative cleavage of the terminal olefin reveals the necessary aldehyde functional group. Additionally, although C11 is in the ketone oxidation state in the natural product, the potential for epimerization2,3 at C10 and other complications suggested that the prudent choice would be to mask C11 as a protected hydroxyl group. The synthesis of 5 began with indiummediated addition of prenyl bromide to 8, a commonly used derivative of the Roche ester,15 to give 9 (Scheme 4).16,17 (10) Available in two steps from methyl acetoacetate: Eggen, M.; Mossman, C. J.; Buck, S. B.; Nair, S. K.; Bhat, L.; Ali, S. M.; Reiff, E. A.; Boge, T. C.; Georg, G. I. J. Org. Chem. 2000, 65, 7792-7799. (11) (a) Lee, B. H.; Biswas, A.; Miller, M. J. J. Org. Chem. 1986, 51, 106-109. (b) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 21572164. (12) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and Sons: New York, 1994; p 56. (13) For a review of chelation-controlled additions to aldehydes, see: Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556-569. (14) Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7, 2937-2940. (15) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348-6359.
J. Org. Chem, Vol. 72, No. 25, 2007 9737
Moslin and Jamison SCHEME 5.
Synthesis of Alkyne 6 via HKR
SCHEME 7.
Possible Binding Mode of 1,6-Enyne 5
SCHEME 8.
Directing Effects of Tethered Alkenes
SCHEME 6. Nickel-Catalyzed Reductive Coupling Reactions of 1,6-Enyne 5
TABLE 1. Discovery of an Olefin-Directing Effect in 1,6-Enynesa entry
phosphine
yield (%)
drb
1 2 3 4
(+)-NMDPP (-)-NMDPP P(o-anisyl)3 None
39 45 52 84
80:20 77:23 80:20 80:20
a In all cases, the reaction was run neat in 350 mol % Et B using 10 mol 3 % Ni(cod)2 and (if employed) 10 mol % phosphine. b Determined by 1H NMR.
Protection of the secondary alcohol followed by selective deprotection of the primary alcohol and the Ley oxidation18 provided 10 in good yield over 3 steps. Treatment of 10 with the Seyferth-Gilbert reagent19 provided a terminal alkyne that was then methylated to yield 5. The third necessary fragment was available from racemic heptene oxide by way of Jacobsen’s hydrolytic kinetic resolution (Scheme 5).20 Addition of a lithium anion derived from propyne to 11 and subsequent conversion to the acetate ester provided 6. Studies of Nickel-Catalyzed Reductive Fragment Coupling Operations. On the basis of data obtained in early model studies,21 we reasoned that (+)-neomenthyldiphenylphosphine ((+)-NMDPP) would be an excellent candidate ligand for stereoselective reductive coupling of 3 and 5 (Scheme 6 and Table 1, entry 1). Although the regioselectivity was much greater than expected,22 the yield in these reactions was disappointingly (16) Arakis, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 18311833. (17) Relative stereochemistry was assigned by comparison of coupling constants of the benzylidine derivatives of the major and minor diastereomers.
(18) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625-1627. (19) (a) Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc. 1967, 89, 4811-4812. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997-4998. (20) (a) Tokunaga, M.; Larrow, J. F.; Kakuchi, F.; Jacobsen, E. N. Science (Washington, DC, U.S.) 1997, 277, 936-938. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315. (21) The model study featured 1-cyclohexyl-propyne and (()-3-(t-butyldimethyl-silanyloxy)-3-phenyl-propionaldehyde and gave 77% yield, with 69:31 regioselectivity and 71:29 dr using (+)-NMDPP. (22) The highest selectivity observed with an alkyne featuring a 2° and a 1° terminus is 85:15 (Scheme 1; eq 3), and frequently lower selectivity is observed. See ref 9.
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low. Moreover, the diastereoselectivity was largely invariant with respect to the ligand, as demonstrated by the fact that both the other enantiomers of NMDPP and an achiral ligand provided the same sense and essentially the same degree of diastereoselectivity (Table 1, entries 2 and 3). The latter result was most unexpected and prompted us to test the reaction in the absence of a phosphine ligand. Not only was this reaction effective, but a significant increase in yield was observed, and the high degree of regio- and diastereocontrol was maintained (Table 1, entry 4). The success of this coupling stands in stark contrast to all of our previous experience with this chemistry, in which we had never observed any coupling product in the absence of a phosphine ligand. Knochel et al. had previously reported the favorable interaction of a distal alkene in nickel-catalyzed cross-coupling reactions of alkyl halides with dialkylzinc reagents.23 On the basis of our own results and this precedent, we proposed that the terminal olefin was coordinating to the nickel center, forcing the aldehyde to bind adjacent to carbon a (Scheme 7).24 This hypothesis was studied in more detail, and we have since determined that the high regioselectivity in phosphine-free nickel-catalyzed reductive coupling reactions is general for and specific to 1,6-enynes, while other enynes failed to react (Scheme 8 and Table 2).25 Unfortunately, the major diastereomer observed in the coupling of 3 and 5 was of the opposite configuration to that found in 1. As the use of a phosphine additive was detrimental to reaction yield and the possibility of achieving efficient reagent control was limited, we were left to consider the impact of the stereocenters of 3 and 5. As C11 is a ketone in (+)-acutiphycin, we had the luxury of using epi-C(11)-5 (13). To probe the (23) (a) Devasagayaraj, A.; Stu¨demann, T.; Knochel, P. Angew. Chem., Int. Ed. 1995, 34, 2723-2725. (b) Giovannini, R.; Stu¨demann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 35443553. (24) The orientation of the aldehyde and mode of diastereoinduction has not been fully elucidated. (25) It was also determined that regioselectivity was reversed by the addition of PCyp3. For complete details, see: (a) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342-15343. (b) Moslin, R. M.; Miller, K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598-7610.
Total Synthesis of (+)-Acutiphycin TABLE 2. Directing Effects of Tethered Alkenesa entry
enyne
N
yield (%)
regioselectivity (A/B)b
1 2 3 4 5
1,31,41,51,61,7-
0 1 2 3 4
